1-carbalkoxy-4-(aminoalkanol) piperazines



ited States Patent Ofiice 3,015,657 Patented Jan. 2, 1962 This invention relates to novel compositions of matter and more particularly to the production of unsymmetrically substituted piperazines.

The compounds embraced bythe present invention possess useful therapeutic properties in that they have been found to exhibit important antitussive activity. In addition, they are useful intermediates for the chemical syntheses of other therapeutic compositions.

It is therefore a primary object of the present invention to provide novel therapeutic compositions.

Another object of the invention is to provide novel unsymmetrically substituted piperazines.

Another object of this invention is to provide novel chemical compositions constituting intermediates for the production of useful therapeutic agents.

Still another object of the invention is to provide a novel method of producing unsymmetrically substituted piperazines.

These and further objects and advantages of the invention and the manner in which they are accomplished will be more apparent from the following description of the class of compounds and the specific examples and methods of obtaining them.

The novel therapeutically and medicinally useful compounds of the present invention are 1-carbalkoxy-4- (aminoalkanol) piperazines and their non-toxic acid addition salts. The free bases may be represented by the following formula:

ROOON t! NOH2CHOHCH2B in which R is an alkyl radical containing from 1 to 4- carbons, n is a number from to 4 and in which E is a member of the group made up of morpholino, pyrrolidino, piperidino, monomethylpipenidino and inwhich'R' and R" each is an alkyl radical containing from 1 to 4 carbons.

The compounds of the structure shown in Formula I are purified by vacuum distillation and as thus prepared are nearly colorless oils.

The compounds of the above structure are soluble in ethanol and in ether. The simplest member,

is quite soluble in water. Also, the corresponding morpholino derivative is soluble in water. In general, increase in molecular weight causes a decrease in water solubility. While the higher members are only slightly soluble in water, all of the compounds of Formula I of the present invention'dissolve readily in dilute hydrochloric acid.

The compounds of structure ROOON |Z NOH2CHOHCH2B of the present invention are prepared by one or more of the following type reactions:

ROOCN l NCH2CHOHCH2 B I (CH3) n BCH2CHOHCH2N l! NCOOR Method No. 1) is the preferred method for all of the syntheses except when B is (CH N.

Method No. (2) can be used for the preparation of all compounds disclosed in the present application.

Method No. (3) was used in the preparation of several compounds but has the disadvantage that ester formation as well as urethane formation may take place. Purification was more difiicult when Reaction No. (3) wasused than in the other syntheses.

In Method No. (1) and Method No. (2) l-carbalkoxypipenazines of the structure R0 0 ON 1/ N-H (III) are used as intermediates. The compounds of structure III were prepared, withslight modification in some cases, by the reaction of ClCOOR with piperazines of the structure according to the procedurereported in an article by T. S. Moore, M. Boyle and V. M. Thorn, J. Chem, Soc., 1929, part I, page 39.

The following examples are illustrative only and are not intended to limit the invention in any way. All parts areby weight unless otherwise stated-. All temperatures are uncorrected and are on the centigrade scale.

EXAMPLE 1 A mixture of 9.25 g. (0.05 mole) of 3-di-n-butylamino- 1,2-epoxypropane, 8.63 g. (0.05 mole) of l carbopropoxypiperazine and 50 ml. of 95% ethanol wasallowedto stand for one week and then'was heated in a water bath at approximately for 8 hours. The reaction mixture was distilled under reduced pressure. l-carbopr0poxy-4-(3-dibutylamino 2 hydroxypropyl)piperazine was obtained in a yield of 11 g. (61%) at 162164 at 0.12 mm.

Similarly, by reaction of 3-di-n-butylamino-1,2-epoxypropane with 1-carbopropoxy-3-methylpiperazine there was obtained l-carbopropoxy 4 (3-dibutylamino-2-hydroxypropyl)-3-methylpiperazine. The l-carbopropoxy- B-methylpiperzine contained mixed with it some l-carbopropoxy-Z-methylpiperazine. This latter product, with the 3-di-n-butylamino-1,2-epoxypropane, yielded 1-carbopropoxy-4-(S-dibutylamino 2 hydroxypropy1)-2-methylpiperazine.

By similar procedure, but by allowing a standing time at room temperature of twoweeks and a heating time in the water bath of 30 hours, S-di-n-butylamino-1,2-epoxypropane and l-carbobutoxy 3,5 dimethylpiperazine yielded l-carbobutoxy-4-(3-dibutylamino-Z-hydroxypropyl)-3,5-dimethylpiperazine. The 1-carbobutoxy-3,5,-dimethylpiperazine contained mixed with it some l-carbobutoxy-2,6-dimethylpiperazine. This latter compound, with the epoxide used just above, yielded l-carbobutoxy- 4-(3-dibutylamino 2 hydroxypropyl)-2,6-dimethylpiperazine.

EXAMPLE 2 A mixture of 4.0 g. of 3-diethylamino-1,Z-epoxypropane and 2.4 g. of 1-carbethoxy-2,3,5,6-tetramethylpiperazine was let stand for 3 weeks with frequent mixing and then was heated in a water bath for 30 hours. On distillation there was obtained 3.0 g. (47%) of l-carbethoxy 4 (3 dimethylamino 2 hydroxypropyl)-2,3,5,6- tetramethylpiperazine, boiling at 166168 at 0.35 mm.

EXAMPLE 3 A mixture of 4.7 g. of 3-piperidino-1,2-epoxypropane and 7.0 g. of 1-carbomethoxy-2,3,5,6-tetramethylpiperazine was allowed to stand for 3 weeks with frequent mixing and was heated on a water bath for 30 hours. On distillation there was obtained 5.5 g. (47%) of l-carbomethoxy-4-(3-piperidino 2 hydroxypropyl)-2,3,5,6- tetramethylpiperazine boiling at 170-172 at 0.45 mm. pressure.

EXAMPLE 4 A mixture of 3.6 g. of 3-morpholino-1,Z-epoxypropane and 4.7 g. of 1-carbethoxy-trans-Z,S-dimethylpiperazine was let stand for one week with frequent mixing and was heated in a water bath for 12 hours. The reaction mixture yielded 6.0 g. (72%) of 1-carbethoxy-4-(3-morpholino-Z-hydroxypropyl)-trans-2,5-dimethylpiperazine at 165-l68 at 0.25 mm. pressure.

EXAMPLE 5 A mixture of 7.0 g. each of 3-morpholino-1,2-epoxypropane and l-carbomethoxy 2,3,5,6 tetramethylpiperazine was allowed to stand for 3 weeks with frequent mixing and was heated for 25 hours in a water bath. On vacuum distillation there was obtained 5.8 g. (49%) of 1-carbomethoxy-4-(3-morpholino 2 hydroxypropyl)- I 2,3,5,6-tetramethylpiperaziue at 179-180 at 0.50 mm.

EXAMPLE 6 A mixture of 5.0 g. (0.029 mole) of l-carbopropoxypiperazine, 2.7 g. (0.029 mole) of epichlorohydrin and 10 ml. of ethanol was allowed to stand at room temperature for 14 hours. To the reaction mixture 10 ml. of 6 N sodium hydroxide was added and the mixture was stirred for 15 minutes. To this basic mixture was added 25 ml. of dirnethylamine (25% in water) and the reaction mixture was allowed to stand for one hour. Another 25 ml. of dimethylamine solution was added and the mixture was allowed to stand for four days. Then 100 m1. of 6 N sodium hydroxide was added and the mixture was extracted with 100 ml. of ether. The ether extract was filtered and the ether was removed by vacuum evaporation. The residue, on distillation yielded 6.0 g. (75%) of 1-carbopropoxy-4-(3-dimethylamino-Z-hydroxypropyl) piperazine, boiling at 144-146 at 0.40 mm. pressure.

4 EXAMPLE 7 A mixture of 5.0 g. (0.025 mole) of l-carbomethoxy- 2,3,5,6-tetramethylpiperazine and 2.8 g. (0.030 mole) of epichlorohydrin was allowed to stand for 8 days. Twenty ml. of butanol was added and the solution was heated in a rotary vacuum evaporator in a water bath at 75 for three hours. To the residue was added 50 ml. of dimethylamine (25 in water) and the mixture was allowed to stand for four days. The mixture was treated with 20 ml. of 6 N sodium hydroxide and was extracted with ml. of ethyl ether. The ether extract was dried over anhydrous potassium carbonate, filtered and vacuum evaporated. The residue on distillation yielded 2.6 g. (33%) of l-carbomethoxy 4 (3 dimethylamino-2-hydroxypropyl) 2,3,5,6 tetramethylpiperazine boiling at -147 at 0.40 mm.

EXAMPLE 8 A mixture of 6.0 g. (0.0347 mole) of carbopropoxypiperazine and 3.7 g. (0.040 mole) of epichlorohydrin was allowed to stand for 12 hours. Twenty ml. of hutanol was added and the mixture was heated in a vacuum evaporator in a water bath at 75 for two hours. The residue was cooled to room temperature and was treated with 15 ml. of 6 N sodium hydroxide over a period of 30 minutes. Then 8 ml. of pyrrolidine was added and the mixture was well agitated. After standing for 12 hours the mixture was heated in the water bath for 20 hours. It was treated with 15 ml. of 6 N sodium hydroxide solution and was extracted with 100 ml. of ethyl ether. The ether layer was dried over anhydrous potassium carbonate and filtered and the ether was vacuum evaporated. The residue on distillation yielded 5.6 g. (5 8%) of l-carbopropoxy-4-(3-pyrrolidino-2-hydroxypropyl) piperazine boiling at -167 at 0.25 mm.

EXAMPLE 9 A mixture of 7.0 g. of 1-carbopropoxy-2,3,5,6-tetramethylpiperazine and 3.0 g. of epichlorohydrin was allowed to stand for 6 days. To the reaction mixture 20 ml. of butanol was added and volatile material was removed by heating in a rotary vacuum evaporator on a water bath for 2.5 hours. To the residue 15 ml. of 6 N sodium hydroxide was added slowly with thorough mixing over a period of 30 minutes. Then 8 ml. of pyrrolidine was added and the products were well mixed. After standing for four hours the reaction mixture was heated for 12 hours in a water bath. It was cooled, treated with 15 ml. of 6 N sodium hydroxide solution and extracted with 100 ml. of ether. The ether was dried over anhydrous potassium carbonate and was removed by vacuum evaporation. On distillation of the residue there was obtained 2.5 g. of 1-carbopropoxy-4-(3-pyrro1indino-2-hydroxypropyl) 2,3,5,6 tetramethylpiperazine, boiling at 168-170 at 0.35 mm.

EXAMPLE 10 After a mixture of 6.0 g. of 1-carbethoxy-cis-2,5-dimethylpiperazine and 3.5 g. of epichlorohydrin had been allowed to stand for 5 days, it was treated with 25 ml. of butanol. Volatile material was removed by heating in a rotary evaporator in a water bath at 75 for four hours. To the residue 15 ml. of 6 N sodium hydroxide solution was added slowly, with shaking. Then 2.8 g. of morpholine was added, the mixture was allowed to stand overnight and was heated on a water bath for 12 hours. The reaction mixture was treated with 15 ml. of 6 N sodium hydroxide and was extracted with 100 ml. of ether. The ether extract was dried over potassium carbonate and vacuum evaporated. The residue on distillation yielded 6.2 g. of 1-carbethoxy-4-(3-morpholino-2-hydroxypropyl)-cis-2,5-dimethylpiperazine, boiling at 168-170 at 0.35 mm.

EXAMPLE 11 A mixture of 7.0 g. of 1-carbopropoxy-2,3,5,6-tetrarnethylpiperazine and 3.0 g. of epichlorohydrin was allowed to stand for days. It was treated with 25 ml. of butanol and volatile material was removed by heating in a rotary evaporator in a water bath at 75 for four hours. sodium hydroxide solution. Then 2.8 g. of morpholine was added and the mixture was allowed to stand for 12 hours. It then was heated in a water bath for hours, cooled and treated with 15' m]. of 6 N sodium hydroxide. The mixture was extracted with 100 ml. of ether. ether layer was dried over potassium carbonate and the ether was vacuum evaporated. The residue was vacuum distilled. Yield of 1carbopropoxy-4-(3-morpholino-2- hydroxypropyl)-2,3,5,6-tetramethylpiperazine boiling at 183-185 at 0.40 mm., 3.0 g. (26%). 15

EXAMPLE 12 To a mixture of 6.0 g. of 1-(3-dibutylamino-2-hydroxypropyl)-trans-2,S-dimethylpiperazine, 1 m1. of triethylamine and 60 m1. of 95% ethanol mechanically stirred minutes of stirring another portion of 50 ml. of 6 N so- 2'.)

dium hydroxide was added. The reaction mixture was extracted with two ml. portions of ether. The combined ether extracts were filtered and the ether was removed by vacuum evaporation. The residue on distillation yielded 2.0 g. (30%) of 1-carbomethoxy-4-(3-dibu- 30 tylamino 2 hydroxypropyl) trans 2,5 dimethylpiperazine, boiling at ISO-153 at 0.25 mm.

EXAMPLE 13 To a mechanically stirred solution of 5.4 g. of 1-[3- (2 methy1piperidino)2 hydroxypropyl] cis 2,5 dimethylpiperazine in 60 ml. of ether in a salt-ice water To the residue was added slowly 15 ml. of 6 N 5 The 10 in 10 ml. of ether. The temperature was kept below 0. The reaction mixture was treated with 20 ml. of 6 N sodium hydroxide over a period of 10 minutes. An additional 50 ml. of 6 N sodium hydroxide solution was added and the reaction mixture was extracted with two 30 m]. portions of ether. The combined ether extracts were filtered and the ether was removed by vacuum evaporation. The residue on vacuum distillation yielded 2.0 g. (29%) of 1-carbomethoxy-4-[3-(2-methylpiperidino)- 2-hydroxypropyl]-cis-2,5-dimethylpiperazine, boiling at 174176 at 0.30 mm.

EXAMPLE 14 A cooled mechanically stirred mixture of 5.2 g. of 1 (3 morpholino 2 hydroxypropyl) cis 2,5 dirnethylpiperazine, 1 ml. of triethylamine and 60 ml. of 95% ethanol was treated Slowly with 1.8 g. of methylchloroformate in 10 ml. of ether, the temperature being kept below 0". Then 15' ml. of 6 N sodium hydroxide was added and the reaction mixture was stirred for 10 minutes. Another portion of sodium hydroxide, 100 ml. of 6 N, was added. The reaction mixture was extracted with two 50 ml. portions of ether. The combined ether extracts were filtered and the ether was removed by vacuum evaporation. The residue on distillation yielded 2.0 g. (30%) of 1-carbomethoxy-4-(3-morpholino-2-hydroxypropyl)-cis-2,5-dimethylpiperazine, boiling at 175- 177 at 0.25 mm. pressure.

The compounds of the present invention form salts with inonganic acids as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid and with organic acids as acetic acid, lactic acid, citric acid, caproic acid, tartaric acid, and thiodisalicylic acid.

Following is a table listing some of the various specific compounds produced, the method used in obtaining the compounds and data for identifying each of the com- I bath was added slowly 1.8 g. of methylchloroformate pounds:

Table l-CARBALKOXY-4-(AMINOALKANOL)-PIPERAZINES Titrable N, B.P., Pressure, Percent? n B R Method 0. mm. Hg

Galcd Found 0... Dimethy1amino-..- PropyL- 2 144-146 10. 25 10. 05 Diethylamino. Methyl 1 152-155 40 10.25 9. 97 d 1 138-140 20 9. 75 9. 86 2 155-157 30 9. 30 9. 21 1 172-178 40 8. 89 8. 90 1 175-179 30 8. 16 8. 11 1 162-4 12 7. 84 7. 66 176-178 20 7. 54 7. 26 1 168-170 9. 75 9. 53 1 205-211 9. 30 9. 23 1 200-205 8. 50 8. 35 1 164-167 10. 33 10. 31 2 165-167.. .25 9. 36 9. 00 1 173-175 70 8. 8. 94 0.-- Piperidino Ethyl... .1 173-177 25 9. 36 9. 10 0. 2-Methy1piperidino d0 1 184-186 80 8. 94 8. 88 0 4-Methylpiperidino Methvl 1 168-171 40 9. 36 9. 47 d0 Ethyl-.. 1 173-175. 35 8. 94 8. 83 1 Dimethylamino. ..d0.. 2 192-193 9. 0 10. 22 9. 72 1--. ..d0 PropyL- 2 148-150 60 9. 75 9. 83 1.-. Diethylamino Ethyl--. 1 162-165 60 9. 3O 8. 68 1.-- -....do Butyl.-. 1 180-185v 50 8. 50 8. 48 1-.. D1buty1am1n0. Ethyl-.. 1 185-188 30 7. 84 7. 64 10.... PropyL- 1 200-202 50 7. 64 7. 75 ..d0.. Butyl... 1 181-182 15 7. 27 6. 64 1. Morphohn Methyl 168-170 25 9. 30 8. 98 1-.. d0. Ethyl-.. 1 210 30 8. 88 8. 64 1--- .d0 Butyl--- 1 197-198 50 8. 16 8. 23 1.-. Pyrrolidino PropyL. 1 175-178 .45 8. 94 9.22 1--. Piperidino. Ethyl. 1 1 74-183 45 8. 94 8. 89 1... .d0 PropyL. 1 187-189 45 8. 56 8. 56 1--. 2--Methylpiperidino Butyl-.. 1 184-186 30 7. 88 8. 30 1-.. B-Methylpiperidino Methyl 1 175-178 40 8. 94 9. 23 1-.. 4-Methylpiperidino Ethyl.-. 1 178-180 45 8. 56 8. 70 2 Diethylamino Butyl--- 1 180-184 50 8. l6 8. 18 2 .(10 Ethyl.-. 1 161-166 50 8. 89 8. 63 2 d0 .d0. 1 162-168 .30. 8.89 8. 70 2. Dimethy1an1ino.. Butyl... 2, -148 50. 8. 89 8. 89 2 Diethylaminm 1 -157 45 9. 30 9. 21 2a. Dipropylamino....- do 1 155-160 25 8. 50 8. 24 2 .(10 Ethyl.-- 2 165-167 35 8.16 7. 70

See footnotes at end oftable.

T able-Continued Titrable N, B.P., Pressure, Percent? 17. B R Method 0. mm. Hg

Calcd Found 2 Di-isopropyleminou do 1 185-187 .45 8.16 7.96 2 -do do 1 175-130 .40 8.16 7.87 3 150-153 .25 7.84 7. 99 3 245-248 8. 7. 84 8. 07 1 173-175 10 7.54 7. 80 1 188-190 50 7. 54 7. 38 3 168-170 18 7. 27 7. 43 1 170-173 10 7. 27 7.07 3 195-191 .10 7.01 7. 33 do 1 188-191 .35 7. 01 7.02 Ethylbuty aminodo 1 176-178 7. 54 7. 99 I 2 Morpholino-.- Methyl. 3 175-177 .25 8.88 8.62 l 1 165-168 .25 s. s. 1 d 2 168-170 35 8. 50 8. 50

3 169-171 .15 8.16 8.05 1, 1 210-212 50 7. 84 8.15 3 188-190 30 7. 84 7. 76 1 193-194 25 7. 7. 94 1 163-165 35 9. 36 9. 93 2 162-163 45 8. 94 8. 84 1 180-182 80 8. 56 9. 07 1 3 .20 8.56 8. 57 3 174-176 .30 8. 56 8.09 1 175-177 45 8. 21 8. 24 1 178-180 .30 7. 88 7. 84 lo 1 182-185 45 7. 58 7. 82 2 hd0 1 185-188 .45 7.58 7.75 2 3-Methylp1per1d1 1 173-175 .45 8. 56 8.86 2 (10 1 168-170 .25 8.21 8.00 2 4-Methylpiper1dino. Butyl.-- 1 190-192 .30 7.05 7.58 4 Dimethylamino MethyL 2 -147 .40 9.30 9. 36 4 Diethylaminm -d0 1 163-165 .30 8.50 8.33 4.-- o Ethyl." 1 166-168 .35 8.16 8.28 4 D1butylam1n0 Methyl. 1 170-175 .40 7. 27 71 27 4 Morpholino d0 1 179-180 .50 8.16 8.10 4 do PropyL- 2 183-180 .40 7.54 7.38 4 -d0 Butyl.-- 1 102-103 .45 7.27 7.16 4 Pyrrolidino PropyL. 2 168-170 .35 7. 88 8.03 4 Piperidilm" Meth 1 170-172 .45 8.21 8.38 4 d0 PropyL- 1 186-188 .50 7.58 7.31 4 3-Methylpiperidino. Butyl 1 182-185 .40 7. 05 7.14 4 4-Mothylpiperidin0- Ethyl 2 -182 .35 7. 58 7. 59 4 do Butyl-.- 1 -194 .40 7. 05 7.20

*Titrated with perehloric acid in acetic acid.

a Parent piperazine, trans 2,5 dirnethyl.

b Parent piperazine, cis 2,5 dirnethyl.

v Parent piperazine, 2,6-dimethyl.

The boiling points in the examples and in the table represent the ranges of temperature over which the samples were collected under widely varying conditions and are for identification purposes only and are not intended to limit the invention.

The compounds of the present invention are useful in medicine in that they possess important antitussive action. Also, the compounds are useful intermediates for chemical syntheses. They are cleaved by hydrolysis in acid solution to yield, after treatment with alkali, compounds of the structure (CH ).I

which are being included in another patent application now undergoing preparation.

The compounds of structure V are in turn valuable intermediates for the synthesis of pharmacologically active and useful compounds. For example, useful bronchial dilators of the structure I) are formed by the reaction of compounds of structure V with distilled Thus, 1-(3-diethylamino-Z-hydroxypropyl)-3,5-dimethylpiperazine reacts with 3-dipropylamino-l,Z-epoxypropane to yield 1-(3-diethy1amino-2-hydroxypropyl)-4-(3-dipropylamino-Z-hydroxypropyl)-3,5-dimethylpiperazine, boiling at 188-191" C. at 0.35 mm. Hg.

The following equations are typical reactions of compounds of structure V to yield other useful products:

CH DH-CH2 45 (CzHshNCHzCHOHCHzN N-H+ CHT'C cis CH;

(CaH5)2CHCOCl- 50 CH:

JHCH2 O (CaHshNCEzcEIoHcHaN N-O--CH(C H )1 CHz-CH 55 cis CH;

(an analgesic) (VII) The above amide was obtained in a yield of 91% by reaction in a well cooled ether solution.

9 The above unsymmetrical piperazine, boiling at 193-195 at 0.35 mm. was obtained in a yield of 68% by reaction with no solvent but in the presence of a trace of water. The mixture was allowed to stand for two days at room temperature with frequent mixing and then was heated in a water bath for 20 hours.

The specific compounds and methods disclosed herein are to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than the foregoing description, and all specific compounds and methods which come within the meaning and range of equivalency of the claims are intended to be embraced therein.

What is claimed and desired to be secured by' the United States Letters Patent is:

1. Compounds selected from the group consisting of (1) those having the formula ROOCN NCHzCHOHCHz-B wherein R is an alkyl radical of from 1 to 4 carbons, n is a whole number up to 4, including zero, and B is a member of the group consisting of morpholino, pyrrolidino, piperidino, monomethylpiperidino and in which R and R" each is an alkyl radical of from 1 to 4 carbons and (2) the therapeutically useful acid addition salts thereof.

10 2. The compound I (CH3) 3. The compound 4. The compound 1' H O OOCN 5. The compound mczoooN NCHzCHOHCHz b eis He 6. The compound 115020001 1 nomononcmmogmn 7. The compound HsCgOOCN NCHCHOHCH2N(C:H5)7

UNITED STATES; PATENT OFF-ICE CERTIFICATE OF CORRECTION Patent No. 3,015,657 January 2, 1962 I Gharles F. Geschickter et al. v 2

It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below. v

Column 2, lines 7. to 10, the lowerright-hand portion of formula (1) should appear asshown below instead of as in the patent: I I 3 n -CI-I CIIoHc I N cooR Signed and sealed this 19th day of June 1962.

(SEAL) Attest: j

DAVID L. LADD ERNEST W. SWIDER Commissioner of Patents Attesting Officer 

1. COMPOUNDS SELECTED FROM THE GROUP CONSISTING OF (1) THOSE HAVING THE FORMULA
 2. THE COMPOUND 